Non-neoplastic and neoplastic hyperproliferative skin disorders are prevalent and present an everincreasing burden to health care providers. Increased exposure of skin to UV light in recent years has contributed to the marked increased incidence of premalignant lesions such as actinic keratoses. Superficial squamous and basal cell carcinoma levels now exceed 700,000 cases per year in the US (American Cancer Society, 1994). Similarly warts (plantar and genital) and other localized hyperproliferative conditions of the skin are extremely prevalent.
At the present time, there are insufficient effective treatment options available to the clinician. Treatment modalities for these conditions include surgical resection or freezing the tissue to destroy rogue cells. These methods are not always the treatment of choice as they are non-selective and, hence, hyperproliferative cells can remain to cause recurrence or normal tissue can be damaged with the development of scar tissue. These techniques are often painful and therefore unacceptable to patients. Exfoliative acidic compounds such as salicylates are used topically to desquamate hyperproliferative skin lesions and kill cells directly, particularly in the treatment of plantar warts. However this treatment is not selective for hyperproliferative cells and is not always curative. The topical application of cytotoxic agents such as bleomycin and 5-fluorouracil (5FU) is used for the treatment of premalignant and malignant lesions and podophyllotoxin for genital warts. There is some concern about the toxicity of these agents, which work by direct cytotoxicity, interfering with DNA synthesis of proliferating cells by a variety of mechanisms. These agents have to be applied extremely carefully to avoid contact with normal skin since normal skin can be irreparably damaged, and systemic absorption of these compounds may also provide a significant risk to the patient. Retinoids, which are vitamin A derivatives, are a recent introduction for the treatment of neoplastic skin lesions. Unfortunately, these compounds are suppressive rather than curative and withdrawal of the drug leads to recurrence.
The epidermis forms the outermost layers of skin. This organ undergoes a process of continuous renewal in which the inner layer of epidermal cells, epidermal keratinocytes, continuously proliferate then undergo terminal differentiation leading to programmed cell death by the cross-linking of cellular proteins by transglutaminase enzymes to form cornified envelopes, which form the stratum corneum. This process is altered in hyperproliferative skin diseases, especially in virally induced warts, actinic keratoses and neoplasms but also in other hyperproliferative conditions (Yuspa S. H., Cancer Res., 54, 1178-1189, 1994, Molecular Biology of the Skin--the keratinocyte, eds Darmon and Blumenberg, Chapter 7, 207-243, 1993).
An object of the present invention is to provide a method of treating hyperproliferative epithelial diseases by the topical application of a class of compounds, which are hydroxylated aromatic protein cross-linking agents. Hyperproliferative epithelial diseases treatable by this method include most skin diseases wherein the growth control mechanisms have been disrupted. Examples of such diseases are papilloma virus infected cells commonly associated with warts and premalignant and malignant superficial neoplasias of the skin. In addition, cervical hyperproliferative conditions can be topically treated by the method of the present invention.
It is another object of the present invention to use cinnamic acid derivatives and analogs thereof including saturated forms thereof and especially methyl 2,5-dihydroxycinnamate in the treatment of hyperproliferative epithelial lesions. Methyl 2,5-dihydroxycinnamate is a preferred member of the class of compounds useful in the present invention and is highly efficacious as a topical formulation in the treatment of hyperproliferative epithelial lesions, particularly in the treatment of basal and squamous cell carcinomas.
It is yet another object of the present invention to use hydrophobic hydroxylated aromatic protein cross-linking compounds in treatment of skin diseases with more cornified lesions, such as plantar warts. These compounds exhibit good tissue penetration and therefore can be used to treat epithelial diseases below the stratum corneum.